Process for production of aromatic amide carboxylic acid derivative

ABSTRACT

The invention provides a method for producing an aromatic amide carboxylic acid derivative represented by the following Formula (2), including a step of reacting an aromatic amide halide derivative represented by the following Formula (1) with carbon monoxide. In the following Formulae (1) and (2), R 1  represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms; X 1  represents a fluorine atom or a cyano group; X 2  represents a halogen atom; and n represents an integer of from 0 to 3.

TECHNICAL FIELD

The invention relates to a method for producing an aromatic amidecarboxylic acid derivative.

BACKGROUND ART

Methods for producing aromatic carboxylic acid derivatives are known inwhich carbon monoxide is inserted into a certain kind of aromatic halidederivative in the presence of a base and water, using a palladiumcompound as a catalyst (see, for example, Japanese Patent ApplicationLaid-Open (JP-A) Nos. 8-104661, 2003-48859, and 2005-220107).

Furthermore, a method for producing an aromatic amide carboxylic acidderivative having an amide bond and a halogen atom, etc., in themolecule thereof is known (see, for example, International PatentPublication No. WO 2010/18857).

SUMMARY OF INVENTION Technical Problem

The inventors have studied industrial methods for producing aromaticamide carboxylic acid derivatives using the methods described in theabove known art. However, the methods require multi-step reactions andare therefore insufficient as industrial production methods.

The invention provides a method that allows for the production of anaromatic amide carboxylic acid derivative having a halogen atom, etc.,through fewer process steps, and a useful intermediate for use in theproduction method.

Solution to Problem

As a result of the intensive studies to develop a method that allows forthe production of an aromatic amide carboxylic acid derivative having ahalogen atom, etc., through fewer process steps, and is applicable forindustrial production, the inventors have found a novel productionmethod which can solve the above-mentioned problems and have achievedthe invention. Furthermore, the inventors have found a usefulintermediate for use in the method for producing an aromatic amidecarboxylic acid derivative according to the invention and have achievedthe invention.

That is, the invention includes the following aspects.

<1> A method for producing an aromatic amide carboxylic acid derivativerepresented by the following Formula (2), including a step of reactingan aromatic amide halide derivative represented by the following Formula(1) with carbon monoxide.

In Formula (1), R¹ represents a hydrogen atom or an alkyl group having 1to 6 carbon atoms; X¹ represents a fluorine atom or a cyano group; andX² represents a halogen atom. n represents an integer of from 0 to 3.

In Formula (2), R¹, X¹, and n have the same definitions as R¹, X¹, and nin Formula (1), respectively.

<2> The method for producing an aromatic amide carboxylic acidderivative according to <1>, further including a step of alkylating anaromatic amide halide derivative represented by the following Formula(3) when R¹ in Formula (1) represents an alkyl group having 1 to 6carbon atoms.

In Formula (3), X¹, X², and n have the same definitions as X¹, X², and nin Formula (1), respectively.

<3> The method for producing an aromatic amide carboxylic acidderivative according to <1>, further including a step of reacting ananiline derivative represented by the following Formula (4) with anaromatic carboxylic acid derivative represented by the following Formula(5) to obtain the aromatic amide halide derivative represented byFormula (1).

In Formula (4), R¹ and X² have the same definitions as R¹ and X² inFormula (1), respectively.

In Formula (5), X¹ and n have the same definitions as X¹ and n inFormula (1), respectively. Y represents a fluorine atom, a chlorineatom, or a bromine atom.

<4> An aromatic amide halide derivative represented by the followingFormula (1).

In Formula (1), R¹ represents a hydrogen atom or an alkyl group having 1to 6 carbon atoms; X¹ represents a fluorine atom or a cyano group; X²represents a halogen atom; and n represents an integer of from 0 to 3.

<5> The aromatic amide halide derivative according to <4>, wherein, inFormula (1), R¹ represents a methyl group, X¹ represents a fluorineatom, X² represents a chlorine atom, and n represents 0 or 1.

Advantageous Effects of Invention

According to the invention, there can be provided a method that allowsfor the production of an aromatic amide carboxylic acid derivativehaving a halogen atom, etc., through fewer process steps, and a usefulintermediate for use in the production method.

DESCRIPTION OF EMBODIMENTS

As used herein, the term “step” indicates not only a separate step butalso a step that is not clearly distinguished from other steps as longas the desired effect of the step is obtained therefrom. As used herein,the notation “to” expressing a numerical range indicates a rangeincluding the numerical values before and after “to”, as the minimumvalue and the maximum value, respectively.

In the definition of the general formulae, the following terms usedherein have the meanings as explained below.

The term “halogen atom” indicates a fluorine atom, a chlorine atom, abromine atom, or an iodine atom, “n-” means normal, “i-” means iso, “s-”means secondary, and “t-” means tertiary.

The term “alkyl group having 1 to 6 carbon atoms” refers to a linear orbranched alkyl group having 1 to 6 carbon atoms, such as a methyl group,an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group,an i-butyl group, an s-butyl group, a t-butyl group, an n-pentyl group,an i-pentyl group, a neopentyl group, a 4-methyl-2-pentyl group, ann-hexyl group or a 3-methyl-n-pentyl group.

In Formula (1) and Formula (2), each of the “alkyl group having 1 to 6carbon atoms” represented by R¹ may have a substituent. The substituentmay be one or more substituents selected from the group consisting of anunsubstituted linear or branched alkyl group having 1 to 6 carbon atoms,an unsubstituted cyclic cycloalkyl group having 3 to 8 carbon atoms, anunsubstituted linear, branched or cyclic alkenyl group having 2 to 6carbon atoms, an unsubstituted linear, branched or cyclic alkynyl grouphaving 2 to 6 carbon atoms, a halogen atom, a phenyl group, an aminogroup, a cyano group, a hydroxy group, an alkyloxy group, a benzyloxygroup, an alkylthio group, a carboxy group, a benzyl group, aheterocyclic group, a phenylsulfonyl group, a phenylcarbonyl group and aphenylamino group.

When the alkyl group having 1 to 6 carbon atoms represented by R¹ hastwo or more substituents, the substituents may be the same as ordifferent from one another. These substituents may each have anadditional substituent where possible, and specific examples of theadditional substituent include the substituents described above.

Specific examples of the “alkyl group having 1 to 6 carbon atoms” havinga substituent include a methoxymethyl group, a benzyloxymethyl group, aphenacyl group, a p-bromophenacyl group, a p-methoxyphenacyl group, atrichloroethyl group, a 2-chloroethyl group, a 2-methylthioethyl group,a 1-methyl-1-phenylethyl group, a cinnamyl group, a benzyl group, a2,4,6-trimethylbenzyl group, an o-nitrobenzyl group, a p-nitrobenzylgroup, a p-methoxybenzyl group, and a 4-picolyl group.

The compounds represented by Formula (1) and Formula (2) according tothe invention may each contain one or more asymmetric carbon atoms orasymmetric centers in their structures, and may therefore exist as twoor more optical isomers. Embodiments of the invention encompass all ofthe optical isomers of the corresponding compounds and mixturescontaining these optical isomers in any proportions.

The compounds represented by Formula (1) and Formula (2) according tothe invention may each contain two or more geometrical isomers derivedfrom a carbon-carbon double bond in their structures. Embodiments of theinvention encompass all of the mixtures containing geometrical isomersof the corresponding compounds in any proportions.

Hereinbelow, the method for producing the aromatic amide carboxylic acidderivative according to the invention, and the compound that can be usedas a production intermediate preferably used in the method and themethod for producing the compound are described, but the invention isnot limited thereto.

The method for producing the aromatic amide carboxylic acid derivativerepresented by the following Formula (2) according to the inventionincludes a carboxylation step in which the aromatic amide halidederivative represented by the following Formula (1) is reacted withcarbon monoxide. The production method may include an additional step asnecessary.

The carboxylation step allows for the production of the desired aromaticamide carboxylic acid derivative through fewer process steps.Furthermore, this production method is applicable for industrialproduction.

The carboxylation step of the production method is not specificallylimited as long as the aromatic amide halide derivative represented byFormula (1) can react with carbon monoxide. In terms of the reactionyield, the carboxylation step is preferably a step in which the reactionis conducted in the presence of palladium or at least one palladiumcompound, and at least one phosphine compound and water, and morepreferably a step in which the reaction is conducted in the presence ofpalladium or at least one palladium compound, and at least one phosphinecompound, at least one inorganic salt and water.

The aromatic amide carboxylic acid derivative represented by Formula (2)produced by the production method according to the invention is suitablyused as an intermediate for producing amide derivatives having prominentpest-control effects, such as those described in International PatentPublication Nos. WO2010/013567 and WO2010/018714.

In Formula (1) and Formula (2), R¹ represents an alkyl group having 1 to6 carbon atoms; X¹ represents a fluorine atom or a cyano group; X²represents a halogen atom; and n, which represents the number of thesubstituent(s) X¹, is an integer of from 0 to 3.

In the carboxylation step of the production method, palladium or atleast one palladium compound is preferably used.

Examples of the form of palladium or the palladium compound used includeinorganic acids, organic acids, supported palladium and colloidalmetals. Any form of palladium or palladium compound can be used withoutany restrictions.

Specific examples of palladium or the palladium compound includepalladium (II) chloride, palladium (II) bromide, palladium (II) iodide,palladium (II) acetate, palladium (II) nitrate, palladium (II)propionate, bis(triphenylphosphine) palladium (II) chloride,bis(triphenylphosphine) palladium (II) bromide, bis(benzonitrile)palladium (II) chloride, bis(triphenylphosphine) palladium (II) acetate,tetrakis(triphenylphosphine) palladium (0), metal palladium, palladiumcarbon, palladium alumina, palladium silica, palladium-barium carbonate,palladium black and colloidal palladium. Among these, palladium acetate(II), palladium chloride (II) and palladium carbon are preferable.

In a case in which palladium or the palladium compound is used in thecarboxylation step, the amount of palladium or the palladium compoundused is not particularly limited, and generally from 0.01% by mol to 10%by mol, preferably from 0.03% by mol to 2% by mol, with respect to theamount of the aromatic amide halide derivative represented by Formula(1).

In the carboxylation step of the production method according to theinvention, at least one phosphine compound is preferably used. Forexample, the phosphine compound functions as a ligand of palladium or apalladium compound, thereby improving the yield of the resultingaromatic amide carboxylic acid derivative.

Examples of the phosphine compound include triisopropylphosphine,tributylphosphine, triphenylphosphine, tris(4-methylphenyl)phosphine,tris(3-methylphenyl)phosphine, tris(2-methylphenyl)phosphine,tris(2-dimethylaminophenyl)phosphine, dimethylphenylphosphine,1,1-bis(dimethylphosphino)methane, 1,2-bis(diethylphosphino)methane,1,2-bis(dimethylphosphino)ethane, 1,2-bis(diethylphosphino)ethane,1,3-bis(dimethylphosphino)propane, 1,4-bis(dimethylphosphino)butane,1,1-bis(diphenylphosphino)methane, 1,2-bis(diphenylphosphino)ethane,1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane and1,5-bis(diphenylphosphino)pentane. Among these,1,3-bis(diphenylphosphino)propane and 1,4-bis(diphenylphosphino)butaneare preferable.

In the production method, each of palladium, the palladium compound andthe phosphine compound may be used singly, or a complex of palladium andthe phosphine compound or a complex of the palladium compound and thephosphine compound prepared in advance may be used.

In a case in which palladium or the palladium compound is used singly,the amount of the phosphine compound added is not specifically limited.For example, the amount of the phosphine compound added may be 1 or moreequivalents, generally 2 to 100 equivalents, with respect to 1equivalent of palladium or the palladium compound. It is preferable that4 to 50 equivalents of the phosphine compound are used.

It is preferable to use at least one inorganic base in the carboxylationstep of the production method as necessary. It is more preferable to useat least one inorganic base selected from the group consisting ofphosphates, acetates, formates and carbonates.

Examples of the inorganic base include phosphates such as dipotassiummonohydrogen phosphate, potassium dihydrogen phosphate, tripotassiumphosphate, disodium monohydrogen phosphate, sodium dihydrogen phosphate,trisodium phosphate, diammonium monohydrogen phosphate, ammoniumdihydrogen phosphate and triammonium phosphate; acetates such aspotassium acetate, sodium acetate and ammonium acetate; formates such aspotassium formate and sodium formate; carbonates such as potassiumcarbonate, sodium carbonate, potassium hydrogen carbonate and sodiumhydrogen carbonate; and alkali metal hydroxides such as lithiumhydroxide, sodium hydroxide and potassium hydroxide. These inorganicbases may be used singly, or in combination of two or more kindsthereof.

In a case in which the inorganic base is used in the carboxylation step,the amount of the inorganic base used is not specifically limited. Theinorganic base may be used in a molar amount of from 0.1 to 100 timesthe molar amount of the aromatic amide halide derivative represented byFormula (1). The inorganic base is preferably used in a molar amount offrom 1 to 10 times the molar amount of to the aromatic amide halidederivative represented by Formula (1).

In the carboxylation step, it is preferable to use at least oneinorganic base selected from the group consisting of phosphates,acetates, formates and carbonates in a molar amount of from 0.1 to 100times the molar amount of the aromatic amide halide derivativerepresented by Formula (1), and it is more preferable to use at leastone inorganic base selected from the group consisting of phosphates,acetates and carbonates in a molar amount of from 1 to 10 times themolar amount of the aromatic amide halide derivative represented byFormula (1).

In the carboxylation step, a base other than the inorganic base may beused with the inorganic base as necessary. Examples of the base otherthan the inorganic base include organic bases such as triethylamine,tri-n-propylamine, tri-n-butylamine, piperidine, pyridine, 2-picoline,3-picoline, 2,6-lutidine, N-methylmorpholine, N-ethylmorpholine,N,N-diethylaniline, N-ethyl-N-methylaniline, diisopropylethylamine,3-methylimidazole, 1,8-diazabicyclo[5.4.0]-7-undecene,1,4-diazabicyclo[2.2.2]octane and 4-dimethylaminopyridine; and metalalcoholates such as sodium methoxide and sodium ethoxide.

In a case in which the base other than the inorganic base is used, thebase is used in a molar amount of from 0.1 to 100 time, preferably from1 to 10 times the molar amount of the aromatic halide derivativerepresented by Formula (1).

In general, carbon monoxide used in the carboxylation step of theproduction method may be any carbon monoxide as long as it can be usedfor organic synthesis reactions. The carboxylation step is conducted atnormal pressure or under increased pressure. For example, the carbonmonoxide pressure may be appropriately selected within the range of from0.1 MPa to 30 MPa. The carbon monoxide pressure is preferably from 0.2MPa to 20 MPa.

The amount of carbon monoxide used in the carboxylation step is notspecifically limited. For example, the molar ratio of carbon monoxide tothe aromatic amide halide derivative represented by Formula (1) is from0.1 to 50, and preferably from 1.0 to 20.0.

Any method of charging a reactor vessel with carbon monoxide may be usedas long as the method is safe and the reaction is not inhibited thereby.Examples thereof include a method in which all of the carbon monoxide isadded at one time at the start of the reaction, a method in which thecarbon monoxide is added in several batches during the reaction, and amethod in which the carbon monoxide is added while keeping the pressurefixed.

The carboxylation step is preferably conducted in the presence of water.The water to be used may be any water as long as the reaction is notaffected thereby.

In a case in which water is used, the amount of water used is notspecifically limited. Water is generally used in a mass amount of from0.1 to 10 times, preferably from 0.1 to 2 times the mass amount of thearomatic amide halide derivative represented by Formula (1).

The carboxylation step may be conducted in the presence of an organicsolvent and water. Any organic solvent may be used as long as thereaction is not significantly inhibited thereby. Examples of the organicsolvent include alkylated aromatic hydrocarbon solvents such as benzene,toluene and xylene; substituted aromatic hydrocarbon solvents such ascyanobenzene and nitrobenzene; aliphatic hydrocarbon solvents such asn-heptane, n-tetradecane and cyclohexane; halogenated aliphatichydrocarbon solvents such as dichloromethane, chloroform and carbontetrachloride; nitriles such as acetonitrile and propionitrile; alcoholsolvents such as methanol, ethanol, isopropyl alcohol, 1-decanol andbenzyl alcohol; linear and cyclic ether solvents such as diethyl ether,dioxane, tetrahydrofuran, 1,2-dimethoxyethane and t-butyl methyl ether;ester solvents such as ethyl acetate and butyl acetate; ketone solventssuch as acetone, cyclohexanone, butanone and methyl isobutyl ketone; andpolar aprotic solvents such as N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolaneand 1,3-dimethyl-2-imidazolidinone.

In terms of the product yield, it is preferable to use at least onesolvent selected from the group consisting of alkylated aromatichydrocarbon solvents, acyclic or cyclic ether solvents and polar aproticsolvents, and it is more preferable to use at least one solvent selectedfrom the group consisting of alkylated aromatic hydrocarbon solvents.

These organic solvents may be used singly, or in combination of or twoor more kinds thereof.

In a case in which the organic solvent is used, the amount of theorganic solvent used is not specifically limited. The organic solvent isgenerally used in a mass amount of from 1 to 10 times the mass amount ofthe aromatic amide halide derivative represented by Formula (1).

Furthermore, in a case in which the organic solvent is used, the ratioof the amount of water to the amount of the organic solvent ispreferably from 10% by mass to 80% by mass, more preferably from 10% bymass to 70% by mass.

It is preferable that the carboxylation step is conducted using, as asolvent, water and at least one organic solvent, with the ratio of theamount of water being from 10% by mass to 80% by mass relative to theamount of the organic solvent. It is more preferable that thecarboxylation step is conducted using water and at least one alkylatedaromatic hydrocarbon as the organic solvent, with the ratio of theamount of water being from 10% by mass 70% by mass relative to theamount of the organic solvent.

The reaction temperature of the carboxylation step may be appropriatelyselected including room temperature under the reaction pressure. Thecarboxylation step can be generally conducted at a temperature of from50° C. to 250° C., preferably at a temperature of from 100° C. to 200°C.

The reaction time may be appropriately selected depending on the scaleof the reaction, the reaction temperature or the like. The reaction timemay be appropriately selected within the range of from several minutesto 96 hours, preferably from 1 hour to 24 hours.

Following the completion of the carboxylation step, anothercarboxylation step may be conducted by separating the resultant aromaticamide carboxylic acid from the organic solvent layer, and adding anotheraromatic amide halide derivative represented by Formula (1) andinorganic salt to the remaining organic solvent layer.

After the completion of the reaction, the aromatic amide carboxylic acidderivative represented by Formula (2) thus obtained may be isolated fromthe reaction mixture by a common separation and purification method suchas extraction, concentration, neutralization, filtration,recrystallization, column chromatography or distillation. Furthermore,the target compound can be used for the next step without isolating itfrom the reaction system.

When R¹ in Formula (1) represents the alkyl group having 1 to 6 carbonatoms, the method for producing the aromatic amide carboxylic acidderivative represented by Formula (2) according to the inventionpreferably includes an alkylation step in which an aromatic amide halidederivative represented by the following Formula (3) is alkylated toobtain an aromatic amide halide derivative represented by Formula (1).

In Formula (3), X¹ represents a fluorine atom or a cyano group; X²represents a halogen atom; and n represents an integer of from 0 to 3.

As a method for alkylating the aromatic amide halide derivativerepresented by Formula (3) to obtain the aromatic amide halidederivative represented by Formula (1), any method usually used foralkylating an amido group may be used without any restrictions.

For example, the aromatic amide halide derivative represented by Formula(3) may be reacted with a predetermined reactant in a solvent using abase to produce the aromatic amide halide derivative represented byFormula (1) in which R¹ is an alkyl group.

As the solvent, any organic solvent may be used as long as thealkylation reaction is not inhibited thereby. Examples thereof includearomatic hydrocarbon solvents such as benzene, toluene, xylene andchlorobenzene; halogenated aliphatic hydrocarbon solvents such asdichloromethane, chloroform and carbon tetrachloride; nitriles such asacetonitrile and propionitrile; linear and cyclic ether solvents such asdiethyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane and t-butylmethyl ether; ester solvents such as ethyl acetate and butyl acetate;ketone solvents such as acetone, cyclohexanone, butanone and methylisobutyl ketone; alcohol solvents such as methanol and ethanol; polaraprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, dimethylsulfoxide, sulfolane and1,3-dimethyl-2-imidazolidinone; and water. These solvents may be usedsingly, or in combination of or two or more kinds thereof. The amount ofthe solvent used is not specifically limited, and the solvent isgenerally used in a mass amount of from 1 to 10 times the mass amount ofthe aromatic amide halide derivative represented by Formula (3).

Examples of the base include organic bases such as triethylamine,tri-n-butylamine, pyridine and 4-dimethylaminopyridine; alkali metalhydroxides such as lithium hydroxide, sodium hydroxide and potassiumhydroxide; carbonates such as sodium hydrogen carbonate, potassiumhydrogen carbonate, sodium carbonate and potassium carbonate; phosphatessuch as trisodium phosphate, tripotassium phosphate, triammoniumphosphate, disodium monohydrogen phosphate, dipotassium monohydrogenphosphate and diammonium monohydrogen phosphate; acetates such as sodiumacetate, potassium acetate and ammonium acetate; metal alcoholates suchas sodium methoxide and sodium ethoxide; and alkali metal hydrides suchas sodium hydride. The base is used in an molar amount of from 0.01 to100 times, preferably from 0.1 to 5 times the molar amount of thearomatic amide halide derivative represented by Formula (3).

As the reactant, an alkylating agent may be used. Examples thereofinclude alkyl halide compounds such as methyl iodide, ethyl bromide,ethyl iodide, n-propyl iodide and 2,2,2-trifluoroethyl iodide; and alkylsulfates such as dimethyl sulfate and diethyl sulfate.

The amount of the reactant used may be appropriately selected within therange of from 1 molar equivalent to 5 molar equivalents, with respect tothe amount of the aromatic amide halide derivative represented byFormula (3). The reactant may be also used as a solvent.

The reaction temperature and the reaction time are not specificallyrestricted. For example, the reaction temperature may be from −80° C. tothe reflux temperature of the solvent used. The reaction time may befrom several minutes to 96 hours. Each of the reaction temperature andthe reaction time can be appropriately selected.

It is preferable that the method for producing the aromatic amidecarboxylic acid derivative represented by Formula (2) further includesan amidation step, in which an aniline derivative represented by thefollowing Formula (4) is reacted with an aromatic carboxylic acidderivative represented by the following Formula (5) to obtain thearomatic amide halide derivative represented by Formula (3).

In Formula (4) and Formula (5), X¹ represents a fluorine atom or a cyanogroup, X² represents a halogen atom, R¹ represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms; n represents an integer of from0 to 3; and Y represents a fluorine atom, a chlorine atom, or a bromineatom.

The aromatic amide halide derivative represented by Formula (3) may beproduced by the amidation reaction of the aniline derivative representedby Formula (4) with the aromatic carboxylic acid derivative representedby Formula (5) in an appropriate solvent or in the absence of solvent.In the amidation step, an appropriate base or solvent can be used.

Any solvent may be used in the amidation step as long as the reaction isnot significantly inhibited thereby. Examples thereof include alkylatedaromatic hydrocarbon solvents such as benzene, toluene and xylene;halogenated aromatic hydrocarbon solvents such as chlorobenzene anddichlorobenzene; substituted aromatic hydrocarbon solvents such ascyanobenzene and nitrobenzene; aliphatic hydrocarbon solvents such asn-heptane, n-tetradecane and cyclohexane; halogenated aliphatichydrocarbon solvents such as dichloromethane, chloroform and carbontetrachloride; substituted aliphatic hydrocarbon solvents such asnitromethane; linear and cyclic ether solvents such as diethyl ether,dioxane, tetrahydrofuran, 1,2-dimethoxyethane and t-butyl methyl ether;ester solvents such as ethyl acetate and butyl acetate; ketone solventssuch as acetone, cyclohexanone, butanone and methyl isobutyl ketone;nitrile solvents such as acetonitrile and propionitrile; polar aproticsolvents such as N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidone, dimethylsulfoxide, sulfolane and1,3-dimethyl-2-imidazolidinone; and water. These solvents may be usedsingly, or in combination of two or more kinds thereof.

The amount of the solvent used is not specifically limited, and thesolvent is generally used in a mass amount of from 1 to 10 times themass amount of the aniline derivative represented by Formula (4).

Examples of the base used in the amidation step include organic basessuch as triethylamine, tri-n-propylamine, tri-n-butylamine, piperidine,pyridine, 2-picoline, 3-picoline, 2,6-lutidine, N-methylmorpholine,N-ethylmorpholine, N,N-diethylaniline, N-ethyl-N-methylaniline,diisopropylethylamine, 3-methylimidazole,1,8-diazabicyclo[5.4.0]-7-undecene, 1,4-diazabicyclo[2.2.2]octane and4-dimethylaminopyridine; alkali metal hydroxides such as lithiumhydroxide, sodium hydroxide and potassium hydroxide; carbonates such assodium carbonate, potassium carbonate, sodium hydrogen carbonate andpotassium hydrogen carbonate; phosphates such as dipotassiummonohydrogen phosphate, potassium dihydrogen phosphate, trisodiumphosphate, tripotassium phosphate, triammonium phosphate, disodiummonohydrogen phosphate, sodium dihydrogen phosphate, diammoniummonohydrogen phosphate and ammonium dihydrogen phosphate; acetates suchas sodium acetate, potassium acetate and ammonium acetate; and metalalcoholates such as sodium methoxide and sodium ethoxide.

The base is used in an molar amount of from 0.01 to 100 times,preferably from 0.1 to 5 times the molar amount of the amount of thearomatic carboxylic acid derivative represented by Formula (5).

Alternatively, the aromatic amide halide derivative can be producedwithout using a base by removing acidic gas byproducts by passing aninert gas such as nitrogen or argon.

The reaction temperature and the reaction time in the amidation step arenot specifically limited. For example, the reaction temperature may befrom −20° C. to the reflux temperature of the solvent used. The reactiontime may be from several minutes to 96 hours. Each of the reactiontemperature and the reaction time can be appropriately selected.

The aromatic carboxylic acid derivative represented by Formula (5) canbe readily produced from a corresponding aromatic carboxylic acidcompound through an ordinary method using a halogenating agent. Examplesof the halogenating agent include thionyl chloride, oxalyl chloride,phosgene, phosphorous oxychloride, phosphorus pentachloride, phosphorustrichloride, thionyl bromide, and phosphorus tribromide.

Alternatively, the aromatic amide halide derivative represented byFormula (3) may be produced by the reaction of an aromatic carboxylicacid compound corresponding to the aromatic carboxylic acid derivativerepresented by Formula (5) with the aniline derivative represented byFormula (4) in the absence of a halogenating agent.

Such method is described in, for example, Chem. Bet page 788 (1970).

Specific examples thereof includes a method using a carbodiimidecondensing agent such as N,N′-dicyclohexylcarbodiimide or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, with an additive such as1-hydroxybenzotriazole or 1-hydroxysuccinimide as needed. A condensingagent other than the carbodiimide condensing agent may be used, andexamples thereof include peptide condensing agents such asN,N-carbonyldi-1H-imidazole, diphenylphosphoryl azide and diethylphosphorocyanidate. These condensing agents may be used singly.

The amount of the condensing agent used is not specifically limited. Forexample, the condensing agent may be used in a molar amount of from 1 to5 times.

As the solvent, any inert solvent may be used as long as the reaction isnot significantly inhibited thereby, and the inert solvent may beappropriately selected from the solvents described above.

The reaction temperature is generally from −50° C. to +100° C.,preferably from −20° C. to +80° C.

An aniline derivative represented by Formula (4) in which R¹ is an alkylgroup may be obtained by reacting, in a solvent, an aniline derivativerepresented by Formula (4) in which R¹ is a hydrogen atom with analdehyde compound or a ketone compound, followed by a reaction under ahydrogen atmosphere in the presence of a catalyst.

Any solvent may be used as long as the reaction is not significantlyinhibited thereby. Examples thereof include aromatic hydrocarbonsolvents such as benzene, toluene, xylene and chlorobenzene; halogenatedaliphatic hydrocarbon solvents such as dichloromethane, chloroform and1,2-dichloroethane; nitrile solvents such as acetonitrile andpropionitrile; linear and cyclic ether solvents such as diethyl ether,dioxane, tetrahydrofuran, 1,2-dimethoxyethane and t-butyl methyl ether;ester solvents such as ethyl acetate and butyl acetate; alcohol solventssuch as methanol and ethanol; polar aprotic solvents such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone,dimethylsulfoxide, sulfolane and 1,3-dimethyl-2-imidazolidinone; andwater. These solvents may be used singly, or in combination of two ormore kinds thereof.

Examples of the catalyst include palladium catalysts such as palladiumcarbon and palladium hydroxide carbon, nickel catalysts such as Raneynickel, cobalt catalysts, platinum catalysts, ruthenium catalysts, andrhodium catalysts.

The amount of the catalyst used is not specifically limited. Forexample, the catalyst may be used in a molar amount of from 0.05 to 0.5times.

Examples of the aldehyde compound include formaldehyde, acetaldehyde,propionaldehyde, fluoroacetaldehyde, difluoroacetaldehyde,trifluoroacetaldehyde, chloroacetaldehyde, dichloroacetaldehyde,trichloroacetaldehyde, and bromoacetaldehyde.

The amount of the aldehyde compound used is not specifically limited.For example, the aldehyde compound may be used in a molar amount of from1 to 3 times.

Examples of the ketone compound include acetone, butanone, and methylisobutyl ketone.

The amount of the ketone compound used is not specifically limited. Forexample, the ketone compound may be used in a molar amount of from 1 to3 times.

The reaction pressure may be appropriately selected within the range offrom 1 atm to 100 atm. The reaction temperature may be appropriatelyselected within the range of from −20° C. to the reflux temperature ofthe solvent used, and the reaction time may be appropriately selectedwithin the range of from several minutes to 96 hours.

Furthermore, an aniline derivative represented by Formula (4) in whichR¹ is an alkyl group can be obtained by reacting, in a solvent, ananiline derivative represented by Formula (4) in which R¹ is a hydrogenatom with an aldehyde compound or a ketone compound, followed bytreatment with a reducing agent.

As the solvent, any solvent may be used as long as the reaction is notsignificantly inhibited thereby. Examples thereof include aromatichydrocarbon solvents such as benzene, toluene, xylene and chlorobenzene;halogenated aliphatic hydrocarbon solvents such as dichloromethane,chloroform and 1,2-dichloroethane; nitrile solvents such as acetonitrileand propionitrile; linear and cyclic ether solvents such as diethylether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane and t-butyl methylether; ester solvents such as ethyl acetate and butyl acetate; alcoholsolvents such as methanol and ethanol; polar aprotic solvents such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone,dimethylsulfoxide, sulfolane and 1,3-dimethyl-2-imidazolidinone; andwater. These solvents may be used singly, or in combination of two ormore kinds thereof.

Examples of the aldehyde compound and the ketone compound include thesame compounds as mentioned above.

Examples of the reducing agent include borohydrides such as sodiumborohydride, sodium cyanoborohydride and sodium triacetate borohydride.

The amount of the reducing agent used is not specifically limited. Forexample, the reducing agent may be used in a molar amount of from 1 to 3times.

The reaction temperature and the reaction time are not specificallylimited. For example, the reaction temperature may be from −20° C. tothe reflux temperature of the solvent used. The reaction time may befrom several minutes to 96 hours. Each of the reaction temperature andthe reaction time may be appropriately selected.

In addition, an aniline derivative represented by Formula (4) in whichR¹ is an alkyl group can be obtained by reacting, in a solvent or in theabsence of solvent, an aniline derivative represented by Formula (4) inwhich R¹ is a hydrogen atom with an aldehyde compound.

As the solvent, any solvent may be used as long as the reaction is notsignificantly inhibited thereby, and examples thereof include aromatichydrocarbon solvents such as benzene, toluene, xylene and chlorobenzene;halogenated aliphatic hydrocarbon solvents such as dichloromethane,chloroform and 1,2-dichloroethane; nitrile solvents such as acetonitrileand propionitrile; linear and cyclic ether solvents such as diethylether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane and t-butyl methylether; ester solvents such as ethyl acetate and butyl acetate; alcoholsolvents such as methanol and ethanol; polar aprotic solvents such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone,dimethylsulfoxide, sulfolane and 1,3-dimethyl-2-imidazolidinone; alcoholsolvents such as methanol and ethanol; inorganic bases such as sulphuricacid and hydrochloric acid; organic acid solvents such as formic acidand acetic acid; and water. These solvents may be used singly, or incombination of two or more kinds thereof.

Examples of the aldehyde compound include formaldehyde, acetaldehyde,and propionaldehyde.

The amount of the aldehyde compound used is not specifically limited.For example, the aldehyde compound may be used in a molar amount of from1 to 3 times.

The reaction temperature and the reaction time is not specificallylimited. For example, the reaction temperature may be from −20° C. tothe reflux temperature of the solvent used. The reaction time may befrom several minutes to 96 hours. Each of the reaction temperature andthe reaction time may be appropriately selected.

Amide derivatives having prominent pest-control effects can beefficiently produced by, for example, converting the aromatic amidecarboxylic acid derivative represented by Formula (2) produced by themethod for producing aromatic amide carboxylic acid derivativesaccording to the invention into an acid chloride and reacting it with aperfluoroalkylaniline derivative.

The aromatic amide halide derivative represented by Formula (1)according to the invention can be suitably used in the method forproducing the aromatic amide carboxylic acid derivative represented byFormula (2). Therefore, the aromatic amide halide derivative representedby Formula (1) is a useful intermediate for the efficient production ofthe amide derivative having a prominent pest-control effect.

Representative examples of the aromatic amide halide derivativesrepresented by Formula (1) according to the invention are shown in Table1 below, but the invention is not limited to these examples. In Table 1,“n-” represents normal, “i-” represents isopropyl, “Me” represents amethyl group, “Et” represents an ethyl group, “n-Pr” represents a normalpropyl group, “i-Pr” represents an isopropyl group, “n-Bu” represents anormal butyl group, “n-Pn” represents a normal pentyl group, “n-hex”represents a normal hexyl group, “CN” represents a nitrile group, “F”represents a fluorine atom, “Cl” represents a chlorine atom, “Br”represents a bromine atom, and “I” represents an iodine atom.

TABLE 1 Compound X¹ Number 2 3 4 5 6 R¹ X² 1 H H H H H H Cl 2 H H H H HMe Cl 3 H H H H H H Cl 4 H H H H H Me Cl 5 H H H H H Et Br 6 H H F H H HCl 7 H H F H H Me Cl 8 H H F H H H Br 9 H H F H H Et Br 10 H CN H H Hn-Pr I 11 H CN H H H Me Cl 12 H CN H H H H Cl 13 F H H H F H Cl 14 F H HH F Me Cl 15 H H CN H H n-Bu Cl 16 H H CN H H n-Pn Br 17 H H CN H Hn-Hex I

EXAMPLES

The present invention is explained below by reference to Examples, butthe scope of the invention is not limited to these Examples. Chemicalshifts for ¹H-NMR are reported in ppm downfield from tetramethylsilanereference. In addition, “s” means singlet, “d” means doublet, “t” meanstriplet, “m” means multiplet, and “brs” means broad singlet. Unlessotherwise specified, “%” means “percent by weight”.

Example 1 Production of N-(3-chloro-2-fluorophenyl)benzamide

Toluene (250 g) and water (150 g) were added to 50.0 g (0.34 mol) of3-chloro-4-fluoroaniline and the mixture was heated to 60° C. Into thisreaction mixture was added dropwise 50.7 g (0.36 mol) of benzoylchloride. At the same time, a 10% aqueous sodium hydroxide solution wasadded dropwise thereto to maintain the pH around 8. After the dropwiseaddition was completed, the mixture was stirred for 2 hours and cooledin ice. The precipitate was filtered, washed with water, and dried toobtain 74.8 g of the title compound (yield: 87%) as a white solid.

¹H-NMR (CDCl₃, δppm) 7.11-7.18 (2H, m), 7.50-7.61 (3H, m), 7.88-7.90(2H, m), 8.05 (1H, brs), 8.38-8.42 (1H, m).

Example 2 Production of N-(3-chloro-2-fluorophenyl)-N-methylbenzamide

Into toluene (60 g) were added 85% potassium hydroxide (2.8 g, 0.05 mol)and 10.0 g (0.40 mol) of N-(3-chloro-2-fluorophenyl)benzamide obtainedabove. While the reaction mixture was heated at reflux, 6.1 g (0.50 mol)of dimethyl sulfate was added dropwise. The reaction was conducted witha dean stark trap to remove the water generated. After the dropwiseaddition was completed, the mixture was stirred for 1 hour and allowedto cool to room temperature. The resultant was mixed with 20 g of a 5%aqueous sodium hydroxide solution and stirred for 1 hour. The mixturewas allowed to separate to give a toluene layer, which was washed with40 g of water. The toluene layer was concentrated under reducedpressure, and the resultant residue was washed with n-hexane to obtain9.97 g of the title compound (yield: 94%) as a white solid.

¹H-NMR (CDCl₃, δppm) 3.42 (3H, s), 6.89-6.93 (2H, m), 7.19-7.33 (6H, m).

Example 3 Production of 2-fluoro-3-(N-methylbenzamide)benzoic acid

A stainless steel autoclave (100 mL) was charged with 1.98 g (0.0075mol) of N-(3-chloro-2-fluorophenyl)-N-methylbenzamide obtained above,1.91 g (0.009 mol) of tripotassium phosphate, 3.0 g of toluene, 2.0 g ofwater, 15.2 mg (0.0677 mmol) of palladium acetate, and 163 mg (0.395mmol) of 1,3-bis(diphenylphosphino)propane. The autoclave was chargedwith carbon monoxide at 0.6 MPa and sealed, and the mixture was stirredat 180° C. for 3 hours. After being cooled to room temperature, theresultant was mixed with ethyl acetate and water and allowed toseparate. The aqueous layer was acidified (to a pH of from 2 to 3) withdilute hydrochloric acid and extracted with ethyl acetate. The aqueouslayer was then adjusted to a pH of from 5 to 6.5 with sodium hydrogencarbonate and extracted with ethyl acetate. The ethyl acetate layerswere combined, washed with saturated brine, and dried over anhydrousmagnesium sulfate. The magnesium sulfate was filtered off, and thefiltrate was concentrated. The resultant residue was purified on silicagel column chromatography (eluent; n-hexane:ethyl acetate=1:2) to obtain1.25 g of the title compound (yield: 61.0%) as a white solid.

¹H-NMR (CDCl₃, δppm) 3.45 (3H, s), 7.08 (1H, brs), 7.21-7.33 (5H, m),7.85-7.88 (1H, brs).

The proton for the carboxylic acid was not observed.

Example 4 Production of 2-fluoro-3-(N-methylbenzamide)benzoic acid

A stainless steel autoclave (200 mL) was charged with 15.0 g (0.055 mol)of N-(3-chloro-2-fluorophenyl)-N-methylbenzamide obtained above, 16.19 g(0.165 mol) of potassium acetate, 9.36 g (0.0935 mol) of potassiumhydrogen carbonate, 32.8 g of toluene, 3.95 g of water, 2.37 g of Pd/C(55.25% wet), and 0.949 g (0.0023 mol) of1,3-bis(diphenylphosphino)propane. The autoclave was charged with carbonmonoxide at 1.4 MPa and sealed, and the mixture was stirred at 180° C.for 7 hours. After being cooled to room temperature, the resultant wasmixed with toluene, water, and a 20% aqueous KOH solution and allowed toseparate. The aqueous layer was acidified to a pH of 1 with 6 Nhydrochloric acid solution to precipitate a solid, which was filteredand dried to obtain 13.46 g of the title compound (yield: 90%) as awhite solid.

Example 5 Production of 2-fluoro-3-benzamide benzoic acid

A stainless steel autoclave (100 mL) was charged with 1.87 g (0.0075mol) of N-(3-chloro-2-fluorophenyl)benzamide obtained above, 1.91 g(0.009 mol) of tripotassium phosphate, 3.0 g of toluene, 2.0 g of water,15.2 mg (0.0677 mmol) of palladium acetate, and 163 mg (0.395 mmol) of1,3-bis(diphenylphosphino)propane. The autoclave was charged with carbonmonoxide at 0.6 MPa and sealed, and the mixture was stirred at 180° C.for 3 hours. After being cooled to room temperature, the resultant wasmixed with ethyl acetate and water and allowed to separate. The organiclayer was washed with a 5% aqueous sodium hydroxide solution. Theaqueous layer was acidified to a pH of 1 with concentrated hydrochloricacid to precipitate a solid, which was filtered and dried to obtain 0.93g of the title compound (yield: 48%) as a light gray solid.

¹H-NMR (DMSO-d₆, δppm) 7.31 (1H, m), 7.55 (2H, m), 7.62 (1H, m), 7.72(1H, m), 7.82 (1H, m), 7.99 (2H, m), 10.2 (1H, s).

Example 6 Production of N-(3-chloro-2-fluorophenyl)-4-fluorobenzamide

In a manner similar to Example 1 using 50.0 g (0.34 mol) of3-chloro-4-fluoroaniline, 57.0 g (0.36 mol) of p-fluorobenzyl chlorideand 300 g of toluene, 82.9 g of the title compound (yield 90%) wasobtained as a white solid.

¹H-NMR (CDCl₃, δppm) 7.13-7.22 (4H, m), 7.89-7.92 (3H, m), 8.35-8.38(1H, m).

Example 7 Production ofN-(3-chloro-2-fluorophenyl)-4-fluoro-N-methylbenzamide

In a manner similar to Example 2 using 40.0 g (0.15 mol) ofN-(3-chloro-2-fluorophenyl)-4-fluorobenzamide obtained above, 26.3 g(0.21 mol) of dimethyl sulfate, 13.4 g (0.24 mol) of 85% potassiumhydroxide and 190 g of toluene, 35.9 g of the title compound (yield:94.5%) was obtained as a white solid.

¹H-NMR (CDCl₃, δppm) 3.41 (3H, s), 6.88-6.91 (2H, s), 6.95-6.98 (2H, m),7.24-7.28 (1H, m), 7.31-7.34 (2H, m).

Example 8 Production of 2-fluoro-3-(4-fluoro-N-methylbenzamide)benzoicacid

A stainless steel autoclave (100 mL) was charged with 1.69 g (0.006 mol)of N-(3-chloro-2-fluorophenyl)-4-fluoro-N-methylbenzamide obtainedabove, 3.66 g (0.021 mol) of dipotassium monohydrogen phosphate, 3.60 gof toluene, 1.85 g of water, 12.2 mg (0.0543 mmol) of palladium acetate,and 130 mg (0.315 mmol) of 1,3-bis(diphenylphosphino)propane. Theautoclave was charged with carbon monoxide at 0.6 MPa and sealed, andthe mixture was stirred at 170° C. for 8 hours. After being cooled toroom temperature, the resultant was mixed with ethyl acetate and waterand allowed to separate. The aqueous layer was acidified (to a pH offrom 2 to 3) with dilute hydrochloric acid and extracted with ethylacetate. The aqueous layer was adjusted to a pH of from 5 to 6.5 withsodium hydrogen carbonate and extracted with ethyl acetate. The ethylacetate layers were combined, washed with saturated brine, and driedover anhydrous magnesium sulfate. The magnesium sulfate was filteredoff, and the filtrate was concentrated under reduced pressure. Theresultant residue was purified on silica gel column chromatography(eluent; n-hexane:ethyl acetate=1:2) to obtain 1.55 g of the titlecompound (yield: 88.7%).

¹H-NMR (CDCl₃, δppm) 3.45 (3H, s), 6.88-6.91 (2H, brs), 7.11-7.14 (1H,m), 7.27-7.35 (3H, m), 7.88-7.91 (1H, m). The proton for the carboxylicacid was not observed.

Example 9 Production of 2-fluoro-3-(4-fluoro-N-methylbenzamide)benzoicacid

A stainless steel autoclave (200 mL) was charged with 15.49 g (0.05 mol)of N-(3-chloro-2-fluorophenyl)-4-fluoro-N-methylbenzamide obtainedabove, 16.19 g (0.165 mol) of potassium acetate, 9.36 g (0.0935 mol) ofpotassium hydrogen carbonate, 32.8 g of toluene, 3.95 g of water, 2.37 gof Pd/C (55.25% wet), and 0.949 g (0.0023 mol) of1,3-bis(diphenylphosphino)propane. The autoclave was charged with carbonmonoxide at 1.4 MPa and sealed, and the mixture was stirred at 180° C.for 7 hours. After being cooled to room temperature, the resultant wasmixed with toluene, water, and a 20% aqueous KOH solution and allowed toseparate. The aqueous layer was acidified to a pH of 1 with 6 Nhydrochloric acid to precipitate a solid, which was filtered and driedto obtain 13.46 g of the title compound (yield: 84%) as a white solid.

Example 10 Production of 2-fluoro-3-(4-fluorobenzamide)benzoic acid

A stainless steel autoclave (100 mL) was charged with 1.61 g (0.006 mol)of N-(3-chloro-2-fluorophenyl)-4-fluorobenzamide obtained above, 3.66 g(0.021 mol) of dipotassium monohydrogen phosphate, 3.60 g of toluene,1.85 g of water, 12.2 mg (0.0543 mmol) of palladium acetate, and 130 mg(0.315 mmol) of 1,3-bis(diphenylphosphino)propane. The autoclave wascharged with carbon monoxide at 0.6 MPa and sealed, and the mixture wasstirred at 180° C. for 5.5 hours. After being cooled to roomtemperature, the resultant was mixed with ethyl acetate and water andallowed to separate. The organic layer was washed with a 5% aqueoussodium hydroxide solution. The aqueous layer was acidified to a pH of 1with concentrated hydrochloric acid to precipitate a solid, which wasfiltered and dried to obtain 0.75 g of the title compound (yield: 45%)as a light gray solid.

¹H-NMR (DMSO-d₆, δppm) 8.07-7.38 (7H, m), 10.3 (1H, s), 13.3 (1H, s).

Example 11 Production of N-(3-chloro-2-fluorophenyl)-3-fluorobenzamide

In a manner similar to Example 1 using 10.0 g (0.069 mol) of3-chloro-4-fluoroaniline, 13.1 g (0.082 mol) of m-fluorobenzoyl chlorideand 50 g of toluene, 16.9 g of the title compound (yield 92%) wasobtained as a white solid.

¹H-NMR (CDCl₃, δppm) 7.12-7.20 (2H, m), 7.26-7.32 (1H, m), 7.49-7.53(1H, m), 7.61-7.65 (2H, m), 8.01 (1H, s), 8.35-8.37 (1H, m).

Example 12 Production ofN-(3-chloro-2-fluorophenyl)-3-fluoro-N-methylbenzamide

To 60 g of toluene were added 10.0 g (0.037 mol) ofN-(3-chloro-2-fluorophenyl)-3-fluorobenzamide obtained above and 3.21 g(0.047 mol) of 85% potassium hydroxide. While the mixture was heated atreflux, 6.13 g (0.047 mol) of dimethyl sulfate was added dropwise. Thereaction was conducted with a dean stark trap to remove the watergenerated. After the dropwise addition was completed, the mixture wasstirred for 1.5 hours and allowed to cool to room temperature. Theresultant was mixed with 30 g of a 5% aqueous sodium hydroxide solution,stirred for 1 hour, and allowed to separate. The toluene layer wasconcentrated under reduced pressure and the resultant residue wasseparated and purified on silica gel column chromatography using NHsilica (eluent; n-hexane:ethyl acetate=4:1 to 2:1) to obtain 8.98 g ofthe title compound (yield: 85%) as a white solid.

¹H-NMR (CDCl₃, δppm) 3.42 (3H, s), 6.97-7.00 (3H, m), 7.00-7.08 (2H, m),7.17-7.18 (1H, m), 7.25-7.28 (1H,m).

Example 13 Production ofN-(3-chloro-2-fluorophenyl)-2,6-difluorobenzamide

In a manner similar to Example 1 using 10.0 g (0.069 mol) of3-chloro-4-fluoroaniline, 14.5 g (0.082 mol) of m-fluorobenzoyl chlorideand 50 g of toluene, 18.8 g of the title compound (yield: 96%) wasobtained as a white solid.

¹H-NMR (CDCl₃, δppm) 7.02-7.06 (2H, in), 7.12-7.20 (2H, m), 7.44-7.50(1H, m), 7.90 (1H, s), 8.34-8.43 (1H, m).

Example 14 Production ofN-(3-chloro-2-fluorophenyl)-2,6-difluoro-N-methylbenzamide

To 60 g of toluene were added 10.0 g (0.039 mol) ofN-(3-chloro-2-fluorophenyl)-2,6-difluorobenzamide obtained above and3.22 g (0.050 mol) of 85% potassium hydroxide. While the mixture washeated at reflux, 6.34 g (0.050 mol) of dimethyl sulfate was addeddropwise. The reaction was conducted with a dean stark trap to removethe water generated. After the dropwise addition was completed, themixture was stirred for 2 hours and allowed to cool to room temperature.The resultant was mixed with 30 g of a 5% aqueous sodium hydroxidesolution, stirred for 1 hour, and allowed to separate. The toluene layerwas concentrated under reduced pressure and the resultant residue waspurified on silica gel column chromatography using NH silica (eluent;n-hexane:ethyl acetate=4:1 to 1:1) to obtain 9.92 g of the titlecompound (yield: 86%) as a white solid.

¹H-NMR (CDCl₃, δppm) 3.42 (3H, s), 6.72-6.75 (2H, m), 6.90-6.94 (1H, m),7.07-7.10 (1H, m), 7.16-7.25 (1H, m).

Example 15 Production of2-fluoro-3-(2,6-difluoro-N-methylbenzamide)benzoic acid

A stainless steel autoclave (100 mL) was charged with 1.80 g (0.006 mol)of N-(3-chloro-2-fluorophenyl)-2,6-difluoro-N-methylbenzamide obtainedabove, 3.66 g (0.021 mol) of dipotassium monohydrogen phosphate, 3.60 gof toluene, 1.85 g of water, 12.2 mg (0.0543 mmol) of palladium acetate,and 130 mg (0.315 mmol) of 1,3-bis(diphenylphosphino)propane. Theautoclave was charged with carbon monoxide at 0.6 MPa and sealed, andthe mixture was stirred at 180° C. for 5.5 hours. After being cooled toroom temperature, the resultant was mixed with ethyl acetate and waterand allowed to separate. The organic layer was washed with a 5% aqueoussodium hydroxide solution.

The aqueous layer was acidified to a pH of 1 with concentratedhydrochloric acid to precipitate a solid, which was filtered and driedto obtain 1.57 g of the title compound (yield: 85%) as a white solid.

¹H-NMR (CDCl₃, δppm) 3.20 (3H, s), 6.99-7.00 (2H, m), 7.18-7.22 (1H, m),7.32-7.38 (1H, m), 7.53-7.71 (1H, m), 7.72-7.74 (1H, m).

Example 16 Production of N-(3-chloro-2-fluorophenyl)-3-cyanobenzamide

In a manner similar to Example 1 using 7.0 g (0.048 mol) of3-chloro-4-fluoroaniline, 9.55 g (0.058 mol) of m-cyanobenzoyl chlorideand 35 g of toluene, 13.4 g of the title compound (quantitative yield)was obtained as a white solid. This compound was used in the nextreaction without further purification.

¹H-NMR (CDCl₃, δppm) 7.14-7.18 (1H, m), 7.20-7.23 (1H, m), 7.66-7.69(1H, m), 7.88-7.89 (1H, m), 8.01 (1H, s), 8.10-8.11 (1H, m), 8.20 (1H,s), 8.32-8.35 (1H, m).

Example 17 Production ofN-(3-chloro-2-fluorophenyl)-3-cyano-N-methylbenzamide

To 60 g of toluene were added 7.0 g (0.026 mol) ofN-(3-chloro-2-fluorophenyl)-3-cyanobenzamide obtained above and 2.19 g(0.033 mol) of 85% potassium hydroxide. While the mixture was heated atreflux, 4.19 g (0.033 mol) of dimethyl sulfate was added dropwise. Thereaction was conducted with a dean stark trap to remove the watergenerated. After the dropwise addition was completed, the mixture wasstirred for 2 hours and allowed to cool to room temperature. Theresultant was mixed with 30 g of a 5% aqueous sodium hydroxide solution,stirred for 1 hour, and allowed to separate. The toluene layer wasconcentrated under reduced pressure and the resultant residue waspurified on silica gel column chromatography using NH silica (eluent;n-hexane:ethyl acetate=3:1 to 2:1) to obtain 3.05 g of the titlecompound (yield: 44%) as a light pink oil.

¹H-NMR (CDCl₃, δppm) 3.44 (3H, s), 7.01-7.02 (2H, m), 7.28-7.31 (1H, m),7.33-7.36 (1H, m), 7.52-7.53 (1H, m), 7.57-7.59 (1H, m), 7.63 (1H, s).

Example 18 Production of 2-fluoro-3-(3-cyano-N-methylbenzamide)benzoicacid

A stainless steel autoclave (100 mL) was charged with 1.65 g (0.006 mol)of N-(3-chloro-2-fluorophenyl)-3-cyano-N-methylbenzamide obtained above,3.66 g (0.021 mol) of dipotassium monohydrogen phosphate, 3.60 g oftoluene, 1.85 g of water, 12.2 mg (0.0543 mmol) of palladium acetate,and 130 mg (0.315 mmol) of 1,3-bis(diphenylphosphino)propane. Theautoclave was charged with carbon monoxide at 0.6 MPa and sealed, andthe mixture was stirred at 180° C. for 5 hours. After being cooled toroom temperature, the mixture was mixed with ethyl acetate and water andallowed to separate. The organic layer was washed with a 5% aqueoussodium hydroxide solution. The aqueous layer was acidified to a pH of 1with concentrated hydrochloric acid to precipitate a solid, which wasfiltered and dried to obtain 0.73 g of the title compound (yield: 41%)as a light green solid.

¹H-NMR (DMSO-d₆, δppm) 3.34 (3H, s), 7.13-7.99 (7H, m).

As illustrated above, the method for producing aromatic amide carboxylicacid derivatives according to the invention allows for the production ofthe desired aromatic amide carboxylic acid derivatives through fewerprocesses.

Japanese Patent Application No. 2011-013410 is herein incorporated byreference in its entirety.

All publications, patent applications, and technical standards mentionedin this specification are herein incorporated by reference to the sameextent as if each individual publication, patent application, ortechnical standard was specifically and individually indicated to beincorporated by reference.

1-3. (canceled)
 4. An aromatic amide halide derivative represented bythe following Formula (1)

wherein, in Formula (1), R¹ represents a hydrogen atom or an alkyl grouphaving 1 to 6 carbon atoms; X¹ represents a fluorine atom; X² representsa chlorine atom; and n represents 0 or
 1. 5. The aromatic amide halidederivative according to claim 4, wherein, in Formula (1), R¹ representsa methyl group.